U.S. patent application number 17/606639 was filed with the patent office on 2022-06-30 for compound for treating autoimmune skin diseases caused by inflammation, and use thereof.
This patent application is currently assigned to GenEros Biopharma Ltd.. The applicant listed for this patent is GenEros Biopharma Ltd.. Invention is credited to Xin-Yuan FU, Xinyu LIU, Chengchen LUFEI, Yi ZHOU.
Application Number | 20220204456 17/606639 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-30 |
United States Patent
Application |
20220204456 |
Kind Code |
A1 |
FU; Xin-Yuan ; et
al. |
June 30, 2022 |
COMPOUND FOR TREATING AUTOIMMUNE SKIN DISEASES CAUSED BY
INFLAMMATION, AND USE THEREOF
Abstract
Disclosed is a compound, a medicament, and a pharmaceutical
composition for treating inflammation induced autoimmune skin
diseases, for example psoriasis. The compound is Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof. the compound Nib1 has a chemical formula of
C.sub.28H.sub.29F.sub.2N.sub.3O. It represents a new treatment
mechanism and can effectively treat inflammation induced autoimmune
skin diseases, for example, non-specific dermatitis such as
psoriasis, with less side effects and convenient route of
administration, achieving a balance between safety and
effectiveness. The compounds can be used for a long time and
improve the quality of life of patients. The compounds, medicament,
and pharmaceutical compositions can significantly improve clinical
symptoms of inflammation induced autoimmune skin diseases, such as
non-specific dermatitis such as psoriasis, such as skin rash, skin
peeling, skin thickening, and epidermal hyperplasia, improve blood
vessel dilation, reduce immune cell infiltration, and etc.
Inventors: |
FU; Xin-Yuan; (Hangzhou,
CN) ; LUFEI; Chengchen; (Hangzhou, CN) ; LIU;
Xinyu; (Hangzhou, CN) ; ZHOU; Yi; (Hangzhou,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GenEros Biopharma Ltd. |
Hangzhou, Zhejiang |
|
CN |
|
|
Assignee: |
GenEros Biopharma Ltd.
Hangzhou, Zhejiang
CN
|
Appl. No.: |
17/606639 |
Filed: |
April 30, 2020 |
PCT Filed: |
April 30, 2020 |
PCT NO: |
PCT/CN2020/088285 |
371 Date: |
October 26, 2021 |
International
Class: |
C07D 235/26 20060101
C07D235/26; A61P 17/06 20060101 A61P017/06; A61K 9/00 20060101
A61K009/00; A61K 9/08 20060101 A61K009/08 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 30, 2019 |
CN |
2019 10366891.5 |
Claims
1. A compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, for use in one or more of the
following: (a) treatment of an inflammation induced autoimmune skin
disease; (b) improvement of skin rash; (c) improvement of skin
peeling; (d) reduction of skin thickening; (e) reduction of
epidermal hyperplasia; (f) improvement of blood vessel dilation;
and (g) reduction of immune cell infiltration; wherein the compound
Nib1 has a structure of ##STR00005## and preferably, the
inflammation induced autoimmune skin disease is non-specific
dermatitis, such as psoriasis, scleroderma, hydroa, and/or alopecia
areata.
2. Use of a compound Nib1, a pharmaceutically acceptable salt
thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, in the
preparation of a medicament for treatment of an inflammation
induced autoimmune skin disease, improvement of skin rash,
improvement of skin peeling, reduction of skin thickening,
reduction of epidermal hyperplasia, improvement of blood vessel
dilation and/or reduction of immune cell infiltration; wherein the
compound Nib1 has a structure of ##STR00006## and preferably, the
inflammation induced autoimmune skin disease is non-specific
dermatitis, such as psoriasis, scleroderma, hydroa, and/or alopecia
areata.
3. A pharmaceutical composition, comprising a compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, for use in one or more of the following: (a)
treatment of an inflammation induced autoimmune skin disease; (b)
improvement of skin rash; (c) improvement of skin peeling; (d)
reduction of skin thickening; (e) reduction of epidermal
hyperplasia; (f) improvement of blood vessel dilation; and (g)
reduction of immune cell infiltration; wherein the compound Nib1
has a structure of ##STR00007## and preferably, the inflammation
induced autoimmune skin disease is non-specific dermatitis, such as
psoriasis, scleroderma, hydroa, and/or alopecia areata; and/or, the
pharmaceutical composition further comprises a pharmaceutically
acceptable carrier, excipient and/or solvent; and/or, the
pharmaceutical composition further comprises a further medicament
for treatment of an inflammation induced autoimmune skin disease,
improvement of skin rash, improvement of skin peeling, reduction of
skin thickening, reduction of epidermal hyperplasia, improvement of
blood vessel dilation and/or reduction of immune cell
infiltration.
4. The pharmaceutical composition of claim 3, wherein the
pharmaceutical composition is in the form of a preparation for
internal or external use; and/or, the pharmaceutical composition is
in the form of an oral preparation or a preparation for external
application; the compound Nib1, a pharmaceutically acceptable salt
thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, in the oral
preparation, is administered at preferably 0.1-1.098 mg/kg per
time, once a day; the compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, in the
preparation for external application is administered at 5-15
mg/cm.sup.2 each time, at least once a day.
5. The pharmaceutical composition of claim 4, wherein when the
pharmaceutical composition is in the form of a preparation for
external application, the preparation for external application
comprises, by weight, 0.2-0.3 parts of the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 9-11 parts of an oil phase, 1.3-2.6 parts of an
emulsifier, 6.5-8.5 parts of a solvent and 25-35 parts of water;
preferably, the compound Nib1, a pharmaceutically acceptable salt
thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof is 0.25 parts by
weight; and/or, the oil phase includes one or more oil phases,
preferably two oil phases; and/or, the oil phase includes a
solidified oil phase and an ordinary oil phase; the solidified oil
phase is preferably 5-6 parts, such as 5.5 parts, and the ordinary
oil phase is preferably 4-5 parts, such as 4.5 parts; the
solidified oil phase is preferably cetostearyl alcohol, and the
ordinary oil phase is preferably medium chain triglycerides;
and/or, the emulsifier includes one or more emulsifiers, and
preferably includes Tween 60 and Span 80, wherein the weight of
Tween 60 is preferably 1-2 parts, such as 1.5 parts, and the weight
of Span 80 is preferably 0.3-0.6 parts, for example 0.35, 0.4 or
0.5 parts; and/or, the solvent includes one or more solvents,
preferably including dimethyl sulfoxide and benzyl alcohol, wherein
the weight of the dimethyl sulfoxide is preferably 2.5-3.5 parts,
such as 3 parts, and the weight of benzyl alcohol is preferably 4-5
parts, for example 4.5 parts; and/or, the weight of the water is
preferably 30 parts or 30.25 parts; and/or, the preparation for
external application further includes acetic acid, and the weight
of the acetic acid is preferably 0.3-0.5 parts, more preferably 0.4
parts; more preferably, the preparation for external application
comprises by weight 0.25 parts of the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 0.4 parts of acetic acid, 5.5 parts of cetostearyl
alcohol, 4.5 parts of medium chain triglycerides, 1.5 parts of
Tween 60, 0.35 parts of Span 80, 3 parts of dimethyl sulfoxide, 4.5
parts of benzyl alcohol, and 30 parts of water; alternatively, the
preparation for external application comprises by weight 0.25 parts
of the compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, 5.5 parts of cetostearyl
alcohol, 4.5 parts of medium chain triglycerides, 1.5 parts of
Tween 60, 0.5 parts of Span 80, 3 parts of dimethyl sulfoxide, 4.5
parts of benzyl alcohol, and 30.25 parts of water.
6. The pharmaceutical composition of claim 5, wherein the
preparation for external application is prepared by mixing the
compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, the oil phase, the emulsifier,
the solvent, and water; preferably, the preparation for external
application can be prepared by first dissolving the compound Nib1,
a pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, in the solvent, followed by adding the oil phase and
the emulsifier, and finally adding water; more preferably, the
temperature of the dissolution is 65-75.degree. C.; and/or, the
dissolution time is 4-6 min; and/or, after adding the oil phase and
the emulsifier, it is placed in an environment with a temperature
of preferably 65-75.degree. C. for preferably 10-20 min; and/or,
the temperature of the water is 65-75.degree. C.; and/or, after
adding the water, the mixture is stirred, preferably until it is
cooled to form a cream.
7. Use of compound Nib1, a pharmaceutically acceptable salt
thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, of claim 1 or
2, or the pharmaceutical composition of any one of claims 3 to 6,
for the treatment of an inflammation induced autoimmune skin
disease; or for improvement of skin rash, improvement of skin
peeling, reduction of skin thickening, reduction of epidermal
hyperplasia, improvement of blood vessel dilation and/or reduction
of immune cell infiltration; preferably, the inflammation induced
autoimmune skin disease is non-specific dermatitis, such as
psoriasis, scleroderma, hydroa, and/or alopecia areata.
8. Use of compound Nib1, a pharmaceutically acceptable salt
thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, of claim 1 or
2, or the pharmaceutical composition of any one of claims 3 to 6,
in the preparation of a medicament for the treatment of an
inflammation induced autoimmune skin disease, improvement of skin
rash, improvement of skin peeling, reduction of skin thickening,
reduction of epidermal hyperplasia, improvement of blood vessel
dilation and/or reduction of immune cell infiltration; preferably,
the inflammation induced autoimmune skin disease is non-specific
dermatitis, such as psoriasis, scleroderma, hydroa, and/or alopecia
areata; and/or, the medicament further comprises a pharmaceutically
acceptable carrier, an excipient and/or a solvent; and/or, the
medicament is in the form of a pharmaceutical composition which
preferably further comprises a further drug for treatment of an
inflammation induced autoimmune skin disease, improvement of skin
rash, improvement of skin peeling, reduction of skin thickening,
reduction of epidermal hyperplasia, improvement of blood vessel
dilation and/or reduction of immune cell infiltration.
9. A method for treatment of an inflammation induced autoimmune
skin disease, improvement of skin rash, improvement of skin
peeling, reduction of skin thickening, reduction of epidermal
hyperplasia, improvement of blood vessel dilation and/or reduction
of immune cell infiltration, comprising using the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, of claim 1 or 2, or the pharmaceutical composition of
any one of claims 3 to 6, for the treatment; preferably, the
inflammation induced autoimmune skin disease is non-specific
dermatitis, such as psoriasis, scleroderma, hydroa, and/or alopecia
areata.
10. A preparation for external application, comprising, by weight,
0.2-0.3 parts of compound Nib1, a pharmaceutically acceptable salt
thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, 9-11 parts of
oil phase, 1.3-2.6 parts of emulsifier, 6.5-8.5 parts of solvent,
and 25-35 parts of water; preferably, the preparation for external
application is useful for one or more of the following: (a)
treatment of an inflammation induced autoimmune skin disease; (b)
improvement of skin rash; (c) improvement of skin peeling; (d)
reduction of skin thickening; (e) reduction of epidermal
hyperplasia; (f) improvement of blood vessel dilation; and (g)
reduction of immune cell infiltration; and/or, the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof is 0.25 parts by weight; and/or, the oil phase
includes one or more oil phases, preferably two oil phases; and/or,
the oil phase includes a solidified oil phase and an ordinary oil
phase. The solidified oil phase is preferably 5-6 parts, such as
5.5 parts, and the ordinary oil phase is preferably 4-5 parts, such
as 4.5 parts. The solidified oil phase is preferably cetostearyl
alcohol, and the ordinary oil phase is preferably medium chain
triglycerides; and/or, the emulsifier includes one or more
emulsifiers, and preferably includes Tween 60 and Span 80, wherein
the weight of Tween 60 is preferably 1-2 parts, such as 1.5 parts,
and the weight of Span 80 is preferably 0.3-0.6 parts, for example
0.35, 0.4 or 0.5 parts; and/or, the solvent includes one or more
solvents, preferably including dimethyl sulfoxide and benzyl
alcohol, wherein the weight of the dimethyl sulfoxide is preferably
2.5-3.5 parts, such as 3 parts, and the weight of benzyl alcohol is
preferably 4-5 parts, for example 4.5 parts; and/or, the weight of
the water is preferably 30 parts or 30.25 parts; and/or, the
preparation for external application further includes acetic acid,
and the weight of the acetic acid is preferably 0.3-0.5 parts, more
preferably 0.4 parts; more preferably, the preparation for external
application comprises by weight 0.25 parts of the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 0.4 parts of acetic acid, 5.5 parts of cetostearyl
alcohol, 4.5 parts of medium chain triglycerides, 1.5 parts of
Tween 60, 0.35 parts of Span 80, 3 parts of dimethyl sulfoxide, 4.5
parts of benzyl alcohol, and 30 parts of water; alternatively, the
preparation for external application comprises by weight 0.25 parts
of the compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, 5.5 parts of cetostearyl
alcohol, 4.5 parts of medium chain triglycerides, 1.5 parts of
Tween 60, 0.5 parts of Span 80, 3 parts of dimethyl sulfoxide, 4.5
parts of benzyl alcohol, and 30.25 parts of water.
11. The preparation for external application of claim 10, wherein
the preparation for external application is prepared by mixing the
compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, the oil phase, the emulsifier,
the solvent, and water; preferably, the preparation for external
application is prepared by first dissolving the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, in the solvent, followed by adding the oil phase and
the emulsifier, and finally adding water; more preferably, the
temperature of the dissolution is 65-75.degree. C.; and/or, the
dissolution time is 4-6 min; and/or, after adding the oil phase and
the emulsifier, it is placed in an environment with a temperature
of preferably 65-75.degree. C. for preferably 10-20 min; and/or,
the temperature of the water is 65-75.degree. C.; and/or, after
adding the water, the mixture is stirred, preferably until it is
cooled to form a cream.
12. A medicament with low side effects for treatment of psoriasis,
comprising compound Nib1 and/or a pharmaceutically acceptable salt
thereof, wherein compound Nib1 has chemical formula of
C.sub.28H.sub.29F.sub.2N.sub.3O and a structure of ##STR00008##
13. The medicament for treatment of psoriasis of claim 12, wherein
the medicament further comprises a pharmaceutically acceptable
carrier, an excipient and/or a solvent; preferably, the medicament
is in the form of a preparation for internal or external use.
14. The medicament for treatment of psoriasis of claim 13, wherein
the medicament is in the form of an oral preparation or a
preparation for external application; preferably, the compound Nib1
in the oral preparation is administered at 0.1-1.098 mg/kg per
time, once a day; and/or, the compound Nib1 in the preparation for
external application is administered at 5-15 mg/cm.sup.2 each time,
at least once a day; more preferably, the preparation for external
application comprises, by weight, 0.2-0.3 parts of Nib1 API,
0.3-0.5 parts of acetic acid, 5-6 parts of oil phase A, 4-5 parts
of oil phase B, 1-2 parts of emulsifier A, 0.3-0.4 parts of
emulsifier B, 2.5-3.5 parts of solvent A, 4-5 parts of solvent B,
and 25-35 parts of water; alternatively, the preparation for
external application comprises, by weight, 0.2-0.3 parts of
Nib1API, 5-6 parts of oil phase A, 4-5 parts of oil phase B, 1-2
parts of emulsifier A, 0.4-0.6 parts of emulsifier B, 2.5-3.5 parts
of solvent A, 4-5 parts of solvent B, and 25-35 parts of water.
15. The medicament for treatment of psoriasis of claim 14, wherein
the oil phase A is cetostearyl alcohol, the oil phase B is medium
chain triglycerides, the emulsifier A is Tween 60, the emulsifier B
is Span 80, the solvent A is dimethyl sulfoxide, and the solvent B
is benzyl alcohol; preferably, the preparation for external
application is prepared by a method comprising steps of: (1)
weighing Nib1 and adding it in a container, then adding acetic acid
to make the acetic acid just over the Nib1 API, and the whole white
solid turns into transparent crystals, followed by adding a mixed
solvents consisting of dimethyl sulfoxide and benzyl alcohol,
stirring at room temperature to dissolve a part of the transparent
crystal, and then placing it in a water bath at 65-75.degree. C.
for 4-6 minutes to dissolve Nib1; (2) adding medium-chain
triglycerides to the solution obtained in step (1); adding
cetostearyl alcohol and emulsifier, and placing in a water bath at
65-75.degree. C. for 10-20 minutes to obtain a transparent oil
phase; and (3) adding water at the same temperature to the
transparent oil phase, taking it out and stirring until it cools to
become a cream; alternatively, the preparation for external
application is prepared by a method comprising steps of: (1)
weighing Nib1 and adding it to a mixed solvent composed of dimethyl
sulfoxide and benzyl alcohol, shaking and stirring, and then
placing it in a water bath at 65-75.degree. C. for 15-25 minutes to
obtain an oil phase solution; (2) adding medium-chain
triglycerides, cetostearyl alcohol, Tween 60 and Span 80 to the oil
phase solution, and then heating and melting in a water bath at
65-75.degree. C. to obtain a transparent oil phase solution; and
(3) adding water at the same temperature to the transparent oil
phase solution, stirring continuously, taking it out and stirring
until it cools to become a cream.
Description
[0001] This application claims the priority of Chinese patent
application 201910366891.5, filed Apr. 30, 2019, which is
incorporated herein by reference in its entirety.
Technical Filed
[0002] The present invention is in the field of medicine and
relates to a compound for the treatment of an inflammation induced
autoimmune skin disease, a medicament or a pharmaceutical
composition comprising the compound, and uses thereof, in
particular to a compound with low side effect for treatment of an
inflammation induced autoimmune skin disease including psoriasis,
medicament or a pharmaceutical composition comprising the compound,
and use thereof in the treatment of an inflammation induced
autoimmune skin disease including psoriasis.
BACKGROUND
[0003] Pimozide (C.sub.28H.sub.29F.sub.2N.sub.3O) is a
diphenylbutylpiperidine antipsychotic with similar effect to
haloperidol, but acting weaker and longer. It only needs to be
taken orally once a day. It shows good efficacy on mania,
hallucinations, delusions, apathy withdrawal, and etc. It is
especially suitable for patients suffering from chronic Tourette's
disease. Pimozide also exhibited calcium antagonism activity.
Long-term use of pimozide has not shown systemic risks, nor does it
regulate hormones and endocrine system (see, Journal of Neurology,
Neurosurgery, and Psychiatry, 1986; 49:791-795). The drug has a
long history of use, and formal clinical trial records showed that
patients had a time of taking the medicine for up to 7 years. If no
serious side effects occur, it can be taken for a long time. It was
reported that Nib1 was used in dermatology for treating body
deformity, metastatic melanoma, trichomoniasis, trigeminal
neuralgia and postherpetic neuralgia (see Pimozide in dermatologic
practice. Am J Clin Dermatol 2004; 5 (5): 339-349). The skin
diseases mentioned were only related to subjective diseases,
malignant tumors, parasites or neurological diseases.
[0004] Autoimmune diseases are diseases caused by damages induced
by immune response of the immune system against the components of
the body. Under the influence of certain factors, the body's tissue
components or the immune system itself have some abnormalities,
causing the immune system to mistake its own components as foreign
objects to attack. The immune system then produces antibodies and
active lymphocytes against some of the body's own components,
damages and destroys its own tissues and organs, leading to the
diseases.
[0005] Inflammation and allergies are one of the main causes of
skin diseases. Among them, autoimmune skin diseases caused by
autoimmune attacks are a kind of autoimmune diseases, mainly
composed of four diseases, i.e., psoriasis, usually involved with
itching scaly skin; scleroderma, mainly affecting the inner layer
of skin tissue and causing thickening of the skin around the hands
and feet; hydroa, characteristic of large blisters filled with pus;
and alopecia areata, mainly affecting the scalp and can lead to
alopecia. Many autoimmune skin diseases are similar to a few other
serious skin diseases, especially at the beginning. Autoimmune skin
diseases are difficult to diagnose in the early stages because they
often look like rashes, allergies, or dry skin spots. These
symptoms usually go away on their own or are cured with ointment. A
formal diagnosis usually requires blood and other tests, and a
confirmed patient often faces a lifetime of treatment.
[0006] Psoriasis is a common chronic and recurring skin disease
with characteristic skin lesions. The pathogenesis of psoriasis is
not yet fully understood, and it is currently believed to be
related to a number of factors including genetic factors (it is a
polygenic genetic disease that is involved with interaction among a
variety of factors such as genetic factors and environmental
factors); immune factors (in recent years, it has been widely
believed that psoriasis may be an immune or inflammation-mediated
disease); infectious factors (studies have confirmed that
streptococcal infection, Staphylococcus aureus infection, and
fungal infection are related to the onset of psoriasis, but it is
unclear whether viral infections are related to the onset of
psoriasis); endocrine factors (pregnancy can make the skin lesions
disappear or reduce, but can also make the skin lesions
deteriorate; endocrine diseases such as thyroid disease and
diabetes have little effect on the disease); mental factors
(patients may experience neuropsychiatric changes, and these
changes can deteriorate existing skin lesions); living habits;
drugs; and environmental factors.
[0007] Studies have found that moisture, infection, drinking,
medication, and mental stress are the main risks for inflammation
induced autoimmune skin diseases, such as non-specific dermatitis,
such as psoriasis. Drugs that may induce or deteriorate
inflammation-induced autoimmune skin diseases (such as non-specific
dermatitis such as psoriasis) include (31 receptor blockers,
non-steroidal anti-inflammatory drugs, lithium salts,
antimalarials, tetracyclines, calcium channel blockers, metformin,
interferon alpha, and etc. Environmental factors are related to the
age of onset, and season and climate play a role in the onset and
recurrence of psoriasis.
[0008] There are currently many treatment methods for inflammation
induced autoimmune skin diseases, such as non-specific dermatitis,
such as psoriasis. However, due to the complicated etiology, the
curative effect of these methods cannot be determined, and they
only improve the symptoms of patients. Traditional therapeutic
drugs, especially for patients with autoimmune skin diseases (such
as non-specific dermatitis such as psoriasis) caused by moderate to
severe inflammation, have many adverse reactions, severe side
effects, and no lasting effects, such as hormones such as
dexamethasone. Macromolecular biologics also suffer from other
safety and drug resistance issues. Due to the above factors or the
high price of some drugs, the use of these drugs is restricted.
SUMMARY
[0009] In order to overcome the disadvantages including adverse
reactions, severe toxic side effects, lack of safety, drug
resistance, and etc. in the treatment of inflammation induced
autoimmune skin diseases, for example, non-specific dermatitis such
as psoriasis and other diseases, the present invention provides a
compound for treating inflammation induced autoimmune skin
diseases, for example, non-specific dermatitis such as psoriasis,
and a medicament, a pharmaceutical composition and use thereof. The
compound, the medicament and the pharmaceutical composition
represent a new treatment mechanism and can effectively treat
inflammation induced autoimmune skin diseases, for example,
non-specific dermatitis such as psoriasis, with less side effects
and convenient route of administration, achieving a balance between
safety and effectiveness. The compounds can be used for a long time
and improve the quality of life of patients. The compounds,
medicament, and pharmaceutical compositions can significantly
improve clinical symptoms of inflammation induced autoimmune skin
diseases, such as non-specific dermatitis such as psoriasis, such
as skin rash, skin peeling, skin thickening, and epidermal
hyperplasia, improve blood vessel dilation, reduce immune cell
infiltration, and etc.
[0010] In order to solve the above technical problems, a first
aspect of the present invention provides compound Nib1 (Pimozide),
a pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, for use in one or more of the following:
[0011] (a) treatment of an inflammation induced autoimmune skin
disease;
[0012] (b) improvement of skin rash;
[0013] (c) improvement of skin peeling;
[0014] (d) reduction of skin thickening;
[0015] (e) reduction of epidermal hyperplasia;
[0016] (f) improvement of blood vessel dilation; and
[0017] (g) reduction of immune cell infiltration;
[0018] wherein the compound Nib1 has a chemical formula of
C.sub.28H.sub.29F.sub.2N.sub.3O and a structure of
##STR00001##
[0019] The present inventors discovered that the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, has a good efficacy for treatment of an inflammation
induced autoimmune skin disease, such as non-specific dermatitis
such as psoriasis, and less side effects compared with traditional
hormone drugs such as dexamethasone, suggesting great potential for
preparing a drug to treat an inflammation induced autoimmune skin
disease, for example, non-specific dermatitis, such as
psoriasis.
[0020] In the prior art, hormonal drugs such as dexamethasone have
relatively large side effects. Using dexamethasone for more than a
few days, common systemic glucocorticoid side effects may occur.
These side effects include: stomach upset, increased sensitivity to
gastric ulcers; increased appetite, resulting in a significant
increase in weight; potential diabetic patients in that glucose
intolerance deteriorating the patient's existing diabetes; mental
illness, including personality changes, irritability, and mania;
long-term treatment of osteoporosis in terms of pathological
fractures (such as hip joints); elevated liver enzymes and fatty
liver lenticular degeneration (usually reversible); common
dependence abstinence syndromes; increased intraocular pressure,
including certain types of glaucoma, and cataracts; dermatological
diseases including acne, allergic dermatitis, dry scales,
ecchymosis, erythema, hard-healing wounds, increased sweating,
rash, dermatoglyph that affects the skin reaction test (skin test)
results; allergic reactions (although rare) including angioedema
(very unlikely, because dexamethasone is given to prevent allergic
reactions) and so on.
[0021] Long-term use of dexamethasone can damage the endocrine
system, leading to atrophy of multiple glands, circulatory failure,
and even paralysis of the lower body or even quadriplegia. It is
caused by endocrine disorders that cause heart and kidney damage.
This type of drug can only be used as an emergency and should not
be used as a long-term anti-inflammatory drug. Generally, the
compound Nib1 in disclosed herein has no systemic risk after
long-term use, and it is not a regulatory hormone of endocrine
system.
[0022] Preferably, the inflammation induced autoimmune skin disease
is non-specific dermatitis, such as psoriasis, scleroderma, hydroa,
and/or alopecia areata.
[0023] In order to solve the above technical problems, a second
aspect of the present invention provides use of compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, in the preparation of a medicament for treatment of
an inflammation induced autoimmune skin disease, improvement of
skin rash, improvement of skin peeling, reduction of skin
thickening, reduction of epidermal hyperplasia, improvement of
blood vessel dilation and/or reduction of immune cell
infiltration;
[0024] wherein the compound Nib1 has a structure of
##STR00002##
[0025] Preferably, the inflammation induced autoimmune skin disease
is non-specific dermatitis, such as psoriasis, scleroderma, hydroa,
and/or alopecia areata.
[0026] In order to solve the above technical problems, a third
aspect of the present invention provides a pharmaceutical
composition comprising compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, for one or more
of the following:
[0027] (a) treatment of an inflammation induced autoimmune skin
disease;
[0028] (b) improvement of skin rash;
[0029] (c) improvement of skin peeling;
[0030] (d) reduction of skin thickening;
[0031] (e) reduction of epidermal hyperplasia;
[0032] (f) improvement of blood vessel dilation; and
[0033] (g) reduction of immune cell infiltration;
[0034] wherein the compound Nib1 has a structure of
##STR00003##
[0035] Preferably, the inflammation induced autoimmune skin disease
is non-specific dermatitis, such as psoriasis, scleroderma, hydroa,
and/or alopecia areata.
[0036] Preferably, the pharmaceutical composition further comprises
a pharmaceutically acceptable carrier, an excipient and/or a
solvent.
[0037] Preferably, the pharmaceutical composition further comprises
a further drug, wherein, the further drug may be a drug for
treating an inflammation induced autoimmune skin disease; and/or
the further drug may also be a drug for improvement of skin rash,
improvement of skin peeling, reduction of skin thickening,
reduction of epidermal hyperplasia, improvement of blood vessel
dilation and/or reduction of immune cell infiltration.
[0038] Preferably, the pharmaceutical composition is in the form of
a preparation for internal or external use.
[0039] Preferably, the pharmaceutical composition is in the form of
an oral preparation or a preparation for external application.
[0040] When the pharmaceutical composition is in the form of an
oral preparation, the compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, in the oral
preparation, is administered at preferably 0.1-1.098 mg/kg per
time, once a day or as needed.
[0041] In the present disclosure, the dosage is generally the
dosage for human body, which is calculated according to the dosage
of the animal experiment of the present invention, and specifically
is the mouse dosage divided by the conversion factor 9.1. However,
those skilled in the art should understand that the dosages within
a generally accepted error range in the art should be also within
the scope of the present invention, for example, the difference is
1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,
16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,
29%, 30%, and etc.
[0042] When the pharmaceutical composition is in the form of a
preparation for external application, the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, in the preparation is administered at a dosage
suitable to cover the lesion area, for example, 5-15 mg/cm.sup.2
each time, at least once a day or as needed. In a preferred
embodiment of the present invention, 62.5 mg of the preparation for
external application is applied daily on a site with an area of
2.times.3 cm for seven consecutive days.
[0043] In a preferred embodiment of the present invention, the
pharmaceutical composition is in the form of a preparation for
external application, and the preparation for external application
comprises, by weight, 0.2-0.3 parts of the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 9-11 parts of an oil phase, 1.3-2.6 parts of an
emulsifier, 6.5-8.5 parts of a solvent and 25-35 parts of
water.
[0044] Preferably, the compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof is 0.25 parts by
weight.
[0045] Preferably, the oil phase includes one or more oil phases,
preferably two oil phases.
[0046] Preferably, the oil phase includes a solidified oil phase
and an ordinary oil phase. The solidified oil phase is preferably
5-6 parts, such as 5.5 parts, and the ordinary oil phase is
preferably 4-5 parts, such as 4.5 parts. The solidified oil phase
is preferably cetostearyl alcohol, and the ordinary oil phase is
preferably medium chain triglycerides.
[0047] In the present invention, the solidified oil phase and the
ordinary oil phase are technical terms in the field of external
application preparations, which have the usual meanings understood
by those skilled in the art. Generally, the ordinary oil phase is
the oil phase conventionally used in the art, excluding the
solidified oil phase, and the solidified oil phase generally refers
to the oil phase that can solidify and shape in the art.
[0048] Preferably, the emulsifier includes one or more emulsifiers,
and preferably includes Tween 60 and Span 80, wherein the weight of
Tween 60 is preferably 1-2 parts, such as 1.5 parts, and the weight
of Span 80 is preferably 0.3-0.6 parts, for example 0.35, 0.4 or
0.5 parts.
[0049] Preferably, the solvent includes one or more solvents,
preferably including dimethyl sulfoxide and benzyl alcohol, wherein
the weight of the dimethyl sulfoxide is preferably 2.5-3.5 parts,
such as 3 parts, and the weight of benzyl alcohol is preferably 4-5
parts, for example 4.5 parts.
[0050] Preferably, the weight of the water is preferably 30 parts
or 30.25 parts.
[0051] Preferably, the preparation for external application further
includes acetic acid, and the weight of the acetic acid is
preferably 0.3-0.5 parts, more preferably 0.4 parts.
[0052] In a preferred embodiment of the present invention, the
preparation for external application comprises by weight 0.25 parts
of the compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, 0.4 parts of acetic acid, 5.5
parts of cetostearyl alcohol, 4.5 parts of medium chain
triglycerides, 1.5 parts of Tween 60, 0.35 parts of Span 80, 3
parts of dimethyl sulfoxide, 4.5 parts of benzyl alcohol, and 30
parts of water.
[0053] In a preferred embodiment of the present invention, the
preparation for external application comprises by weight 0.25 parts
of the compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, 5.5 parts of cetostearyl
alcohol, 4.5 parts of medium chain triglycerides, 1.5 parts of
Tween 60, 0.5 parts of Span 80, 3 parts of dimethyl sulfoxide, 4.5
parts of benzyl alcohol, and 30.25 parts of water.
[0054] In the present invention, the cetostearyl alcohol is
cetostearyl alcohol commonly used in the field. In a preferred
embodiment of the present invention, the cetostearyl alcohol used
was purchased from Hunan Erkang Pharmaceutical Co., Ltd. (catalog
#F20170000297).
[0055] Preferably, the preparation for external application is
prepared by mixing the compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, the oil phase,
the emulsifier, the solvent, and water. Generally, it is formulated
into a cream. In the present invention, the ointment can be
prepared by routine methods in the field, with or without changes,
as long as it can achieve a transdermal effect and can be used
externally.
[0056] More preferably, the preparation for external application
can be prepared by first dissolving the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, in the solvent, followed by adding the oil phase and
the emulsifier, and finally adding water.
[0057] Even more preferably, the temperature of the dissolution is
65-75.degree. C.
[0058] Even more preferably, the dissolution time is 4-6 min.
[0059] Even more preferably, after adding the oil phase and the
emulsifier, it is placed in an environment with a temperature of
preferably 65-75.degree. C. for preferably 10-20 min.
[0060] Even more preferably, the temperature of the water is
65-75.degree. C.
[0061] Even more preferably, after adding the water, the mixture is
stirred, preferably until it is cooled to form a cream.
[0062] In a preferred embodiment of the present invention, the
preparation for external application is prepared by a method
comprising the following steps:
[0063] (1) weighing Nib1 and adding it in a container, then adding
acetic acid to make the acetic acid just over the Nib1 API, and the
whole white solid turns into transparent crystals, followed by
adding a mixed solvents consisting of dimethyl sulfoxide and benzyl
alcohol, stirring at room temperature to dissolve a part of the
transparent crystal, and then placing it in a water bath at
65-75.degree. C. for 4-6 minutes to dissolve Nib1;
[0064] (2) adding medium-chain triglycerides to the solution
obtained in step (1); adding cetostearyl alcohol and emulsifier,
and placing in a water bath at 65-75.degree. C. for 10-20 minutes
to obtain a transparent oil phase; and
[0065] (3) adding water at the same temperature to the transparent
oil phase, taking it out and stirring until it cools to become a
cream.
[0066] In a preferred embodiment of the present invention, the
preparation for external application is prepared by a method
comprising the following steps:
[0067] (1) weighing Nib1 and adding it to a mixed solvent composed
of dimethyl sulfoxide and benzyl alcohol, shaking and stirring, and
then placing it in a water bath at 65-75.degree. C. for 15-25
minutes to obtain an oil phase solution;
[0068] (2) adding medium-chain triglycerides, cetostearyl alcohol,
Tween 60 and Span 80 to the oil phase solution, and then heating
and melting in a water bath at 65-75.degree. C. to obtain a
transparent oil phase solution; and
[0069] (3) adding water at the same temperature to the transparent
oil phase solution, stirring continuously, taking it out and
stirring until it cools to become a cream.
[0070] In order to solve the above technical problems, a fourth
aspect of the present invention provides use of compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, as provided in the first or second aspect of the
present invention, or the pharmaceutical composition as provided in
the third aspect of the present invention, for treatment of an
inflammation induced autoimmune skin disease, or use of compound
Nib1, a pharmaceutically acceptable salt thereof, a solvate
thereof, a solvate of a pharmaceutically acceptable salt thereof,
or a crystal form thereof, as provided in the first or second
aspect of the present invention, or the pharmaceutical composition
as provided in the third aspect of the present invention, for
improvement of skin rash, improvement of skin peeling, reduction of
skin thickening, reduction of epidermal hyperplasia, improvement of
blood vessel dilation and/or reduction of immune cell
infiltration.
[0071] Preferably, the inflammation induced autoimmune skin disease
is non-specific dermatitis, such as psoriasis, scleroderma, hydroa,
and/or alopecia areata.
[0072] In order to solve the above technical problems, a fifth
aspect of the present invention provides use of compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, as provided in the first or second aspect of the
present invention, or the pharmaceutical composition as provided in
the third aspect of the present invention, in the preparation of a
medicament for treatment of an inflammation induced autoimmune skin
disease, or for improvement of skin rash, improvement of skin
peeling, reduction of skin thickening, reduction of epidermal
hyperplasia, improvement of blood vessel dilation and/or reduction
of immune cell infiltration.
[0073] Preferably, the inflammation induced autoimmune skin disease
is non-specific dermatitis, such as psoriasis, scleroderma, hydroa,
and/or alopecia areata.
[0074] Preferably, the medicament further comprises a
pharmaceutically acceptable carrier, an excipient and/or a
solvent.
[0075] Preferably, the medicament is in the form of a
pharmaceutical composition which preferably further comprises a
further drug for treating an inflammation induced autoimmune skin
disease; and/or the pharmaceutical composition preferably comprises
a further drug for improvement of skin rash, improvement of skin
peeling, reduction of skin thickening, reduction of epidermal
hyperplasia, improvement of blood vessel dilation and/or reduction
of immune cell infiltration.
[0076] In order to solve the above technical problems, a sixth
aspect of the present invention provides a method for treatment of
an inflammation induced autoimmune skin disease for example in a
subject in need thereof, and/or a method for improvement of skin
rash for example in a subject in need thereof, improvement of skin
peeling for example in a subject in need thereof, reduction of skin
thickening for example in a subject in need thereof, reduction of
epidermal hyperplasia for example in a subject in need thereof,
improvement of blood vessel dilation for example in a subject in
need thereof and/or reduction of immune cell infiltration for
example in a subject in need thereof, comprising using compound
Nib1, a pharmaceutically acceptable salt thereof, a solvate
thereof, a solvate of a pharmaceutically acceptable salt thereof,
or a crystal form thereof, as provided in the first or second
aspect of the present invention, or the pharmaceutical composition
as provided in the third aspect of the present invention for the
treatment, or administering to the subject a therapeutically
effective amount of compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, as provided in
the first or second aspect of the present invention, or the
pharmaceutical composition as provided in the third aspect of the
present invention.
[0077] Preferably, the inflammation induced autoimmune skin disease
is non-specific dermatitis, such as psoriasis, scleroderma, hydroa,
and/or alopecia areata.
[0078] The present invention further provides a method for treating
a subject in need of administering a medicament for treatment of an
inflammation induced autoimmune skin disease, improvement of skin
rash, improvement of skin peeling, reduction of skin thickening,
reduction of epidermal hyperplasia, improvement of blood vessel
dilation and/or reduction of immune cell infiltration, comprising
administering to the subject a therapeutically effective amount of
compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, as provided in the first or
second aspect of the present invention, or the pharmaceutical
composition as provided in the third aspect of the present
invention.
[0079] In order to solve the above technical problems, a seventh
aspect of the present invention provides a preparation for external
application, comprising, by weight, 0.2-0.3 parts of compound Nib1,
a pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 9-11 parts of oil phase, 1.3-2.6 parts of emulsifier,
6.5-8.5 parts of solvent, and 25-35 parts of water.
[0080] Preferably, the preparation for external application is
useful for one or more of the following: (a) treatment of an
inflammation induced autoimmune skin disease; (b) improvement of
skin rash; (c) improvement of skin peeling; (d) reduction of skin
thickening; (e) reduction of epidermal hyperplasia; (f) improvement
of blood vessel dilation; and (g) reduction of immune cell
infiltration.
[0081] Preferably, the compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof is 0.25 parts by
weight.
[0082] Preferably, the oil phase includes one or more oil phases,
preferably two oil phases.
[0083] Preferably, the oil phase includes a solidified oil phase
and an ordinary oil phase. The solidified oil phase is preferably
5-6 parts, such as 5.5 parts, and the ordinary oil phase is
preferably 4-5 parts, such as 4.5 parts. The solidified oil phase
is preferably cetostearyl alcohol, and the ordinary oil phase is
preferably medium chain triglycerides.
[0084] Preferably, the emulsifier includes one or more emulsifiers,
and preferably includes Tween 60 and Span 80, wherein the weight of
Tween 60 is preferably 1-2 parts, such as 1.5 parts, and the weight
of Span 80 is preferably 0.3-0.6 parts, for example 0.35, 0.4 or
0.5 parts.
[0085] Preferably, the solvent includes one or more solvents,
preferably including dimethyl sulfoxide and benzyl alcohol, wherein
the weight of the dimethyl sulfoxide is preferably 2.5-3.5 parts,
such as 3 parts, and the weight of benzyl alcohol is preferably 4-5
parts, for example 4.5 parts.
[0086] Preferably, the weight of the water is preferably 30 parts
or 30.25 parts.
[0087] Preferably, the preparation for external application further
includes acetic acid, and the weight of the acetic acid is
preferably 0.3-0.5 parts, more preferably 0.4 parts.
[0088] More preferably, the preparation for external application
comprises by weight 0.25 parts of the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 0.4 parts of acetic acid, 5.5 parts of cetostearyl
alcohol, 4.5 parts of medium chain triglycerides, 1.5 parts of
Tween 60, 0.35 parts of Span 80, 3 parts of dimethyl sulfoxide, 4.5
parts of benzyl alcohol, and 30 parts of water.
[0089] More preferably, the preparation for external application
comprises by weight 0.25 parts of the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, 5.5 parts of cetostearyl alcohol, 4.5 parts of medium
chain triglycerides, 1.5 parts of Tween 60, 0.5 parts of Span 80, 3
parts of dimethyl sulfoxide, 4.5 parts of benzyl alcohol, and 30.25
parts of water.
[0090] Preferably, the preparation for external application is
prepared by mixing the compound Nib1, a pharmaceutically acceptable
salt thereof, a solvate thereof, a solvate of a pharmaceutically
acceptable salt thereof, or a crystal form thereof, the oil phase,
the emulsifier, the solvent, and water. Generally, it is formulated
into a cream. In the present invention, the ointment can be
prepared by routine methods in the field, with or without changes,
as long as it can achieve a transdermal effect and can be used
externally.
[0091] More preferably, the preparation for external application
can be prepared by first dissolving the compound Nib1, a
pharmaceutically acceptable salt thereof, a solvate thereof, a
solvate of a pharmaceutically acceptable salt thereof, or a crystal
form thereof, in the solvent, followed by adding the oil phase and
the emulsifier, and finally adding water.
[0092] Even more preferably, the temperature of the dissolution is
65-75.degree. C.
[0093] Even more preferably, the dissolution time is 4-6 min.
[0094] Even more preferably, after adding the oil phase and the
emulsifier, it is placed in an environment with a temperature of
preferably 65-75.degree. C. for preferably 10-20 min.
[0095] Even more preferably, the temperature of the water is
65-75.degree. C.
[0096] Even more preferably, after adding the water, the mixture is
stirred, preferably until it is cooled to form a cream.
[0097] In a preferred embodiment of the present invention, the
preparation for external application is prepared by a method
comprising the following steps:
[0098] (1) weighing Nib1 and adding it in a container, then adding
acetic acid to make the acetic acid just over the Nib1 API, and the
whole white solid turns into transparent crystals, followed by
adding a mixed solvents consisting of dimethyl sulfoxide and benzyl
alcohol, stirring at room temperature to dissolve a part of the
transparent crystal, and then placing it in a water bath at
65-75.degree. C. for 4-6 minutes to dissolve Nib1;
[0099] (2) adding medium-chain triglycerides to the solution
obtained in step (1); adding cetostearyl alcohol and emulsifier,
and placing in a water bath at 65-75.degree. C. for 10-20 minutes
to obtain a transparent oil phase; and
[0100] (3) adding water at the same temperature to the transparent
oil phase, taking it out and stirring until it cools to become a
cream.
[0101] In a preferred embodiment of the present invention, the
preparation for external application is prepared by a method
comprising the following steps:
[0102] (1) weighing Nib1 and adding it to a mixed solvent composed
of dimethyl sulfoxide and benzyl alcohol, shaking and stirring, and
then placing it in a water bath at 65-75.degree. C. for 15-25
minutes to obtain an oil phase solution;
[0103] (2) adding medium-chain triglycerides, cetostearyl alcohol,
Tween 60 and Span 80 to the oil phase solution, and then heating
and melting in a water bath at 65-75.degree. C. to obtain a
transparent oil phase solution; and
[0104] (3) adding water at the same temperature to the transparent
oil phase solution, stirring continuously, taking it out and
stirring until it cools to become a cream.
[0105] In order to solve the above technical problems, the present
invention also provides a kit, comprising a package A which is
compound Nib1, a pharmaceutically acceptable salt thereof, a
solvate thereof, a solvate of a pharmaceutically acceptable salt
thereof, or a crystal form thereof, as provided in the first or
second aspect of the present invention, or the pharmaceutical
composition as provided in the third aspect of the present
invention, and a package B which is a further drug for the
treatment of inflammation induced autoimmune skin diseases, or for
improvement of skin rash, improvement of skin peeling, reduction of
skin thickening, reduction of epidermal hyperplasia, improvement of
blood vessel dilation and/or reduction of immune cell infiltration.
The packages A and B can be used simultaneously, or sequentially in
the sequence of A to B or B to A as determined as needed.
[0106] In order to solve the above technical problems, the present
invention also provides a medicament with low side effects for
treatment of psoriasis, comprising compound Nib1 and/or a
pharmaceutically acceptable salt thereof, wherein compound Nib1 has
chemical formula of C.sub.28H.sub.29F.sub.2N.sub.3O and a structure
of
##STR00004##
[0107] Preferably, the medicament for treatment of psoriasis
further comprises a pharmaceutically acceptable carrier, an
excipient and/or a solvent.
[0108] Preferably, the medicament for treatment of psoriasis is in
the form of a preparation for internal or external use.
[0109] Preferably, the medicament for treatment of psoriasis is in
the form of an oral preparation or a preparation for external
application.
[0110] Preferably, the compound Nib1 in the oral preparation is
administered at 0.1-1.098 mg/kg per time, once a day.
[0111] Preferably, the compound Nib1 in the preparation for
external application is administered at a dosage suitable to cover
the lesion area, for example, 5-15 mg/cm.sup.2 each time, at least
once a day or as needed.
[0112] Preferably, the preparation for external application
comprises, by weight, 0.2-0.3 parts of Nib1 API, 0.3-0.5 parts of
acetic acid, 5-6 parts of oil phase A, 4-5 parts of oil phase B,
1-2 parts of emulsifier A, 0.3-0.4 parts of emulsifier B, 2.5-3.5
parts of solvent A, 4-5 parts of solvent B, and 25-35 parts of
water.
[0113] Also preferably, the preparation for external application
comprises, by weight, 0.2-0.3 parts of Nib1API, 5-6 parts of oil
phase A, 4-5 parts of oil phase B, 1-2 parts of emulsifier A,
0.4-0.6 parts of emulsifier B, 2.5-3.5 parts of solvent A, 4-5
parts of solvent B, and 25-35 parts of water.
[0114] More preferably, the oil phase A is cetostearyl alcohol, the
oil phase B is medium chain triglycerides, the emulsifier A is
Tween 60, the emulsifier B is Span 80, the solvent A is dimethyl
sulfoxide, and the solvent B is benzyl alcohol.
[0115] Further preferably, the preparations for external
application are prepared respectively by the following methods.
[0116] Method a (Using Acetic Acid)
[0117] (1) weighing Nib1 and adding it in a container, then adding
acetic acid to make the acetic acid just over the Nib1 API, and the
whole white solid turns into transparent crystals, followed by
adding a mixed solvents consisting of dimethyl sulfoxide and benzyl
alcohol, stirring at room temperature to dissolve a part of the
transparent crystal, and then placing it in a water bath at
65-75.degree. C. for 4-6 minutes to dissolve Nib1;
[0118] (2) adding medium-chain triglycerides to the solution
obtained in step (1); adding cetostearyl alcohol and emulsifier,
and placing in a water bath at 65-75.degree. C. for 10-20 minutes
to obtain a transparent oil phase; and
[0119] (3) adding water at the same temperature to the transparent
oil phase, taking it out and stirring until it cools to become a
cream.
[0120] Method B (Acetic Acid Free)
[0121] (1) weighing Nib1 and adding it to a mixed solvent composed
of dimethyl sulfoxide and benzyl alcohol, shaking and stirring, and
then placing it in a water bath at 65-75.degree. C. for 15-25
minutes to obtain an oil phase solution;
[0122] (2) adding medium-chain triglycerides, cetostearyl alcohol,
Tween 60 and Span 80 to the oil phase solution, and then heating
and melting in a water bath at 65-75.degree. C. to obtain a
transparent oil phase solution; and
[0123] (3) adding water at the same temperature to the transparent
oil phase solution, stirring continuously, taking it out and
stirring until it cools to become a cream.
Definition of Terminologies
[0124] The term "pharmaceutically acceptable" means that salts,
solvents, excipients, etc. are generally non-toxic, safe, and
suitable for use by patients. The "patient" is preferably a mammal,
more preferably a human.
[0125] The term "pharmaceutically acceptable salt" refers to a salt
prepared from a compound of the present invention, a medicament or
a pharmaceutical composition containing the compound, with a
relatively non-toxic, pharmaceutically acceptable acid or base.
When the compound of the present invention, a medicament or a
pharmaceutical composition containing the compound, contains a
relatively acidic functional group, a base addition salt can be
obtained by contacting neutral form of the compound with a
sufficient amount of a pharmaceutically acceptable base in a pure
solution or a suitable inert solvent. Pharmaceutically acceptable
base addition salts include, but are not limited to, lithium salt,
sodium salt, potassium salt, calcium salt, aluminum salt, magnesium
salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine
salt. When the drug of the present invention contains a relatively
basic functional group, an acid addition salt can be obtained by
contacting the neutral form of the drug with a sufficient amount of
a pharmaceutically acceptable acid in a pure solution or a suitable
inert solvent. The pharmaceutically acceptable acids include
inorganic acids, including but are not limited to, hydrochloric
acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic
acid, phosphoric acid, phosphorous acid, sulfuric acid, and the
like. The pharmaceutically acceptable acids include organic acids,
including but not limited to, acetic acid, propionic acid, oxalic
acid, isobutyric acid, maleic acid, malonic acid, benzoic acid,
succinic acid, suberic acid, fumaric acid, lactic acid, mandelic
acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid,
citric acid, salicylic acid, tartaric acid, methanesulfonic acid,
isonicotinic acid, acidic citric acid, oleic acid, tannic acid,
pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid,
fumaric acid, gluconic acid, sugar acid, formic acid,
ethanesulfonic acid, pamoic acid (i.e., 4,
4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (such as
glutamic acid, arginine), and etc. When the drug of the present
invention contains relatively acidic and relatively basic
functional groups, it can be converted into a base addition salt or
an acid addition salt. For details, see Berge et al.,
"Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19
(1977) or Handbook of Pharmaceutical Salts: Properties, Selection,
and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH,
2002).
[0126] The "more" in the term "one or more" may refer to 2, 3, 4,
5, 6, 7, 8, 9, or greater.
[0127] The compound, the medicament or the pharmaceutical
composition of the present invention can be administered in a unit
dosage form, and the route of administration can be parenteral or
non-parenteral, such as oral, topical, intravenous injection,
intramuscular injection, subcutaneous injection, nasal cavity, oral
mucosa, eyes, lungs, respiratory tract, skin, vagina, rectum, etc.,
preferably by oral or external application.
[0128] The dosage form for administration may be a liquid, a solid
or a semi-solid dosage form. Liquid dosage forms can be solutions
(including true solutions and colloidal solutions), emulsions
(including o/w type, w/o type and multiple emulsion), suspensions,
injections (including water injections, powder injections and
infusions), eye drops, lotion and liniment. Solid dosage forms can
be tablets (including ordinary tablets, enteric-coated tablets,
buccal tablets, dispersible tablets, chewable tablets, effervescent
tablets, orally disintegrating tablets), capsules (including hard
capsules, soft capsules, enteric-coated capsules), granules,
powders, pellets, dripping pills, suppositories, films, patches,
aerosol, powder inhalation, sprays, and etc. Semi-solid dosage
forms can be ointments, gels, pastes, and etc.
[0129] The medicament or pharmaceutical composition of the present
invention can be made into ordinary preparations, and can also be
made into sustained-release preparations, controlled-release
preparations, targeted preparations and various particle delivery
systems.
[0130] "Pharmaceutical composition" refers to mixing one or more of
the compounds of the present invention or their pharmaceutically
acceptable salts, solvates, hydrates or prodrugs with other
chemical ingredients, such as pharmaceutically acceptable carriers.
The purpose of the pharmaceutical composition is to facilitate the
process of administration to animals.
[0131] "Pharmaceutically acceptable carrier" refers to an inactive
ingredient in a pharmaceutical composition that does not cause
significant irritation to the organism and does not interfere with
the biological activity and properties of the administered
compound, such as but not limited to, calcium carbonate, calcium
phosphate, various sugars (such as lactose, mannitol, etc.),
starch, cyclodextrin, stearic acid, cellulose, carbonate, acrylic
acid polymer or methacrylic acid polymer, gels, water, polyethylene
glycol, propylene glycol, ethylene glycol, EZ oil or hydrogenated
EZ oil or polyethoxylated hydrogenated EZ oil, sesame oil, corn
oil, peanut oil, and etc.
[0132] The pharmaceutical composition, in addition to a
pharmaceutically acceptable carrier, may also include auxiliary
agents commonly used in pharmacology, such as antibacterial agents,
antifungal agents, antimicrobial agents, stabilizing agents,
colorants, solubilizers, thickeners, surfactants, complexing
agents, proteins, amino acids, fats, carbohydrates, vitamins,
minerals, trace elements, sweeteners, pigments, flavors or their
combination.
[0133] The term "treatment" refers to therapeutic therapy. When
referring to a specific disease, treatment refers to (1)
alleviating one or more biological manifestations of the disease or
disorder, (2) interfering with (a) one or more points in the
biological cascade causing or inducing the disease, or (b)) one or
more biological manifestations of the disorder, (3) improvement of
one or more symptoms, effects or side effects related to the
disorder, or one or more symptoms, effects or side effects related
to its treatment, or (4) slowing down the development or one or
more biological manifestations of the disease.
[0134] The term "solvate" refers to a substance formed by combining
the compound of the present invention with a stoichiometric or
non-stoichiometric solvent. The solvent molecules in the solvate
can exist in an ordered or non-ordered arrangement. The solvents
include but are not limited to water, methanol, ethanol and the
like.
[0135] The "pharmaceutically acceptable salt" and "solvate" in the
term "a solvate of a pharmaceutically acceptable salt" are defined
as above, and the latter refers to a substance formed by combining
a salt prepared from a compound of the present invention with a
relatively non-toxic, pharmaceutically acceptable acid or base,
with a stoichiometric or non-stoichiometric solvent. The "solvate
of a pharmaceutically acceptable salt" includes, but is not limited
to, the hydrochloric acid monohydrate of the compound of the
present invention.
[0136] The terms "compound", "pharmaceutically acceptable salt",
"solvate" and "solvate of pharmaceutically acceptable salt" may
exist in crystalline or amorphous forms. The term "crystal form"
means that the ions or molecules are arranged in strictly
periodical manner in a three-dimensional space in a certain way,
and occur periodically at intervals. Due to the above-mentioned
periodic arrangement, there may be multiple crystal forms, i.e.,
polymorphism. The term "amorphous" means that the ions or molecules
present in a disorderly distribution state, that is, there is no
periodic arrangement between the ions and molecules.
[0137] In the present invention, the "including", "containing" or
"comprising" may mean that in addition to the ingredients listed,
there are other ingredients; it may also mean "consisting of", that
is, only including the ingredients listed and without including
other ingredients.
[0138] The present invention is advantageous over the prior art in
that it represents a new treatment mechanism and can effectively
treat inflammation induced autoimmune skin diseases, for example,
non-specific dermatitis such as psoriasis, with less side effects
and convenient route of administration, achieving a balance between
safety and effectiveness. The compounds can be used for a long time
and improve the quality of life of patients. The compounds,
medicament, and pharmaceutical compositions can significantly
improve clinical symptoms of inflammation induced autoimmune skin
diseases, such as non-specific dermatitis such as psoriasis, such
as skin rash, skin peeling, skin thickening, and epidermal
hyperplasia, improve blood vessel dilation, reduce immune cell
infiltration, and etc.
BRIEF DESCRIPTION OF THE DRAWINGS
[0139] FIG. 1 shows the changes of the animal body weight in
Example 1 during the experiment.
[0140] FIG. 2 shows the clinical scoring data of the rash of the
psoriasis model in Example 1.
[0141] FIG. 3 is the clinical score data of the peeling symptoms of
the psoriasis model in Example 1.
[0142] FIG. 4 is the clinical score data of the skin thickening
symptoms of the psoriasis model in Example 1.
[0143] FIG. 5 is the data of the total clinical score of the
psoriasis model in Example 1.
[0144] FIG. 6 is the comparison result of the area under the
clinical total score curve of the psoriasis model in Example 1.
[0145] FIG. 7 shows the staining results of the skin pathological
section of the normal group in Example 1 (animal number G1-309,
100.times. magnification).
[0146] FIG. 8 shows the staining results of the skin pathological
section of the normal group in Example 1 (animal number G1-316,
100.times. magnification).
[0147] FIG. 9 shows the staining results of the skin pathological
section of the normal group in Example 1 (animal number G1-317,
100.times. magnification).
[0148] FIG. 10 shows the staining results of the skin pathological
section of the model group in Example 1 (animal number G2-315,
100.times. magnification).
[0149] FIG. 11 shows the staining results of the skin pathological
section of the model group in Example 1 (animal number G2-331,
100.times. magnification).
[0150] FIG. 12 shows the staining results of the skin pathological
section of the model group in Example 1 (animal number G2-382,
100.times. magnification).
[0151] FIG. 13 shows the staining results of pathological sections
of the skin in the dexamethasone treatment group in Example 1
(animal number G3-312, 100.times. magnification).
[0152] FIG. 14 shows the staining results of pathological sections
of the skin in the dexamethasone treatment group in Example 1
(animal number G3-333, 100.times. magnification).
[0153] FIG. 15 shows the staining results of pathological sections
of the skin in the dexamethasone treatment group in Example 1
(animal number G3-334, 100.times. magnification).
[0154] FIG. 16 shows the staining results of the skin pathological
section of the Nib1 treatment group in Example 1 (animal number
G4-322, 100.times. magnification).
[0155] FIG. 17 shows the staining results of the skin pathological
section of the Nib1 treatment group in Example 1 (animal number
G4-328, 100.times. magnification).
[0156] FIG. 18 shows the staining results of the skin pathological
section of the Nib1 treatment group in Example 1 (animal number
G3-346, 100.times. magnification).
[0157] FIG. 19 shows the scoring results of the pathological
section in Example 1.
[0158] FIG. 20 shows the change of animal body weight in the
disease model of Example 2.
[0159] FIG. 21 shows the rash score of the disease model in Example
2.
[0160] FIG. 22 shows the peeling symptom score of the disease model
in Example 2.
[0161] FIG. 23 shows the skin thickening symptom score of the
disease model in Example 2.
[0162] FIG. 24 is the total clinical score of the disease model in
Example 2.
[0163] FIG. 25 shows the results of the area under the total
clinical score curve (AUC) in Example 2.
[0164] FIG. 26 is a pathological section of the skin of the normal
group in Example 2 (animal G1-3, 100.times. magnification, H&E
staining).
[0165] FIG. 27 is a pathological section of the skin of the normal
group in Example 2 (animal G1-25, 100.times. magnification, H&E
staining).
[0166] FIG. 28 is a skin pathological section of the normal group
in Example 2 (animal G1-57, 100.times. magnification, H&E
staining).
[0167] FIG. 29 is a pathological section of the skin of the
treatment group of the external application preparation in Example
2 (animal G5-5, 100.times. magnification, H&E staining).
[0168] FIG. 30 is a pathological section of the skin of the
treatment group of the external application preparation in Example
2 (animal G5-43, 100.times. magnification, H&E staining).
[0169] FIG. 31 is a pathological section of the skin of the
treatment group of the external application preparation in Example
2 (animal G5-9, 100.times. magnification, H&E staining).
[0170] FIG. 32 is a skin pathological section of the control group
of the external application preparation of Example 2 (animal G6-10,
100.times. magnification, H&E staining).
[0171] FIG. 33 is a skin pathological section of the control group
of the external application preparation of Example 2 (animal G6-21,
100.times. magnification, H&E staining).
[0172] FIG. 34 is a skin pathological section of the control group
of the external application preparation of Example 2 (animal G6-28,
100.times. magnification, H&E staining).
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0173] The present invention will be described further in reference
to the examples.
[0174] Efficacy Verification of Nib1 in Animal Models of
Psoriasis
Example 1. Treatment of Psoriasis by Oral Administration of
Nib1
[0175] 1. Reagents
[0176] 5% Imiquimod ointment, Aldara, 3M Pharmaceuticals;
Dexamethasone ointment: Shanghai Sanjiu Pharmaceutical; PEG300,
Sigma, catalog number 90878. Nib1 (pimozide): Sigma (P1793).
[0177] 2. Protocol
[0178] Female BALB/c mice (purchased from Shanghai SLACK Laboratory
Animal Co., Ltd, administered at 6 weeks of age) were randomly
divided into groups after adapting to the environment. Except for
the normal control group, the rest of the animals received
imiquimod ointment (5%) externally to induce the establishment of a
psoriasis model. Specifically, the mice were shaved off same area
of the back hair and applied with 62.5 mg of imiquimod ointment
daily for seven consecutive days. Animals received different
treatment programs, weighed daily, orally or externally applied
with drugs once, and recorded with disease progression score.
[0179] The specific grouping information is shown in Table 1. Both
the vehicle control group and the Nib1 treatment group received
oral gavage of the same volume of drugs, formulated with 30%
PEG300, and the Nib1 group was given a dose of 10 mg/kg.
Dexamethasone ointment was used as a positive treatment drug and
received 70 mg smear treatment once a day. The disease progression
score is evaluated on a scale of 0-4 based on three indicators,
rash, peeling, and thickening (0: no symptoms; 1: mild symptoms; 2:
moderate symptoms; 3: significant symptoms; 4: very significant
symptoms). At the end of the experiment, the animals were
sacrificed, and pathological section analysis was performed on the
skin samples of the back lesions. The scoring standards are shown
in Table 2.
TABLE-US-00001 TABLE 1 Groups and Treatments Modeling agent for
Animals Group external Treatment Dosing Regimen Groups (n) Names
use dose Routes Frequency G1 5 Normal None None None None G2 10
Vehicle PO 62.5 mg None oral Once a day 5% for 7 imiquimod
consecutive ointment, days G3 10 DEX cream once a day 70 mg
external Once a day Topical for seven for 7 consecutive consecutive
days days G4 10 Nib1 10 mpk 10 mg/kg oral Once a day PO for 7
consecutive days
TABLE-US-00002 TABLE 2 Scoring Standards of pathological sections
Items Scores Corneum abscess 1.5 parakeratosis 0.5-1.5
hyperkeratosis 0.5 Epidermis length of omentum ridge 0.5-1.5
acanthosis 1 lack of stratum granulosum 1 Dennis immune cell
filtration in dermis 0.5-1 papilla blockage 1 papilla thinning
0.5
[0180] 3. Results
[0181] 3.1 Body Weights
[0182] As shown in FIG. 1 and Table 3, the body weights of the
animals in the dexamethasone topical treatment group were
significantly reduced, indicating that the drug has greater toxic
and side effects, while in the Nib1 oral group, body weights
decreased slightly in the first two days, but recovered quickly,
which was similar to the control group and within the acceptable
range, suggesting Nib1 has a toxic and side effect significantly
less than that of dexamethasone.
TABLE-US-00003 TABLE 3 Statistical significance analysis of body
weight day Group 0 1 2 3 4 5 6 7 DEX vs. ns * ns ns * ** **** ****
Vehicle Nib1 vs * ns ns ns ns * ** ** Vehicle * p < 0.05, ** p
< 0.01, *** p < 0.001, **** p < 0.0001, t-test, compared
with the vehicle control group, ns means no statistically
significant difference.
[0183] 3.2. Nib1 Oral Treatment Improves Symptoms of the
Disease
[0184] The clinical scoring of three indicators including skin
rash, peeling and thickening were recorded and shown as statistical
average value and .+-.standard error by day. The results are shown
in FIGS. 2-4 and Tables 4-6. With daily use of imiquimod ointment
on the skin, the model group showed gradually increasing clinical
symptoms, and the rash reached a peak around the 3rd day and
remained until the end of the model. The Nib1 oral administration
group showed a slightly reduced rash, which was significantly
different in the first three days (FIG. 2, Table 4). The peeling
phenomenon in the model group gradually increased with time,
reached a peak on the fifth day, and then decreased. Nib1 group
could significantly reduce the peeling phenomenon, reaching a peak
on the 4th day and maintaining a relatively low level to the end
point (FIG. 3, Table 5). The skin thickening of the model group had
been increasing, while the Nib1 group showed the same trend, but
the thickening level was significantly reduced on the 4th, 5th, and
6th days (FIG. 4, Table 6). The total score of the three indicators
showed that the Nib1 group had significantly lower clinical
symptoms than the disease model group (FIG. 5, Table 7).
TABLE-US-00004 TABLE 4 statistical significance analysis of rash
scores day Group 0 1 2 3 4 5 6 7 DEX vs. ns ** **** **** **** ****
**** **** Vehicle Nib1 vs ns **** * ** ns ns ns ns Vehicle * p <
0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, t-test,
compared with the vehicle control group, ns means no statistically
significant difference.
TABLE-US-00005 TABLE 5 statistical significance analysis of peeling
scores day Group 0 1 2 3 4 5 6 7 DEX vs. ns ns ns **** **** ****
**** *** Vehicle Nib1 vs ns ns ns *** *** **** ** ns Vehicle * p
< 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001,
t-test, compared with the vehicle control group, ns means no
statistically significant difference.
TABLE-US-00006 TABLE 6 statistical significance analysis of skin
thickening scores day Group 0 1 2 3 4 5 6 7 DEX vs. ns **** ****
**** **** **** **** **** Vehicle Nib1 vs ns ** ns * *** *** ** ns
Vehicle * p < 0.05, ** p < 0.01, *** p < 0.001, **** p
< 0.0001, t-test, compared with the vehicle control group, ns
means no statistically significant difference.
[0185] The results of comprehensive evaluation of the three
clinical indicators are shown in FIG. 5 and Table 7. Nib1 oral
treatment can significantly reduce the clinical symptoms of
psoriasis.
TABLE-US-00007 TABLE 7 statistical significance analysis of total
clinical scores day Group 0 1 2 3 4 5 6 7 DEX vs. ns **** **** ****
**** **** **** **** Vehicle Nib1 vs ns **** ** **** **** *** ** ns
Vehicle * p < 0.05, ** p < 0.01, *** p < 0.001, **** p
< 0.0001, t-test, compared with the vehicle control group, ns
means no statistically significant difference.
[0186] The calculation result of the area under the clinical total
score curve (AUC) is shown in FIG. 6, showing the quantitative
reduction effect of the curative effect. Compared with the disease
model group, the oral administration of Nib1 could significantly
reduce the disease progression, and the quantitative analysis
indicated a 32.2% remission.
[0187] 3.3 Results of Pathological Sections
[0188] The pathological sections of animal skin were stained with
eosin. The 100.times. magnified pictures are shown in FIGS. 7-18.
Three samples were selected for each group. Compared with the
normal control group, the disease model group showed significant
epidermal hyperplasia, immune cell infiltration, destruction of the
epidermal layered structure, and abnormal blood vessel structure.
Nib1 group can improve epidermal hyperplasia and reduce immune cell
infiltration.
[0189] The pathological sections were scored according to the
scoring system in Table 2, and the results are shown in FIG. 19.
Nib1 treatment group showed a statistically significant treatment
effect, reaching a 32.5% remission effect (p<0.01).
[0190] Note: The data were shown as average value.+-.standard
error. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001,
one-way ANOVA, compared with the vehicle control group.
Example 2. Therapeutic Effect of Nib1 for External Use on Animal
Psoriasis Disease Model
[0191] 1. Reagents
[0192] 5% Imiquimod ointment, Aldara, 3M Pharmaceuticals,
H20160079; Dexamethasone ointment: Shanghai Sanjiu Pharmaceutical.
Cetylstearyl alcohol, purchased from Hunan Erkang Pharmaceutical,
F20170000297.
[0193] 2. Preparation for External Application
[0194] There are two formulations designed for the preparation for
external application, and the formulation FLL-15-21-2 is shown in
Table 8.
TABLE-US-00008 TABLE 8 Composition of formulation FLL-15-21-2
Formulation FLL-15-21-2 Content Proportions Batch Materials Effects
(mg) % (g) Nib1 API 25.0 0.5% 0.25 acetic acid solvents and 40.0
0.8% 0.40 salt-forming excipients of API cetostearyl oil phase
matrix 550.0 11.0% 5.50 alcohol for solidification medium chain
ordinary oil 450.0 9.0% 4.50 triglycerides phase solution Tween 60
emulsifier 150.0 3.0% 1.50 Span 80 emulsifier 35.0 0.7% 0.35
dimethyl solvents and 300.0 6.0% 3.00 sulfoxide penetration
enhancers for API benzyl solvents and 450.0 9.0% 4.50 alcohol
preservatives for API purified water water 3000.0 60.0% 30.00 Total
/ 5000.0 100.0% 50.00
[0195] The formulation FLL-15-21-2 of the preparation for external
application is formulated as follows.
[0196] (1) weighing the prescription amount of API in a beaker, and
then adding the prescription amount of acetic acid; when adding,
the acetic acid just surpasses the API powder, and the whole is
changed from a white solid to a slightly sticky crystal; then
adding a mixed solvent of the prescription amounts of dimethyl
sulfoxide and benzyl alcohol, a small part of the transparent
crystal being dissolved by stirring at room temperature, and then
the whole being placed in a water bath at 70.degree. C. for about 5
minutes; the API was dissolved into the solvent; after cooling, the
API did not precipitate.
[0197] (2) adding the prescription amount of medium-chain
triglycerides to the above solution, the API did not precipitate;
then adding the prescription amount of cetostearyl alcohol and the
rest of emulsifiers, and placing it in a 70.degree. C. water bath
for about 15 minutes to obtain a transparent oil phase solution; at
the same time, putting the water in a 70.degree. C. water bath to
keep warm.
[0198] (3) adding water at the same temperature to the above oil
phase solution; the mixture became a white emulsion after the
addition; taking it out and keeping stirring until it cooled to
become a cream; finally, a pH test paper was used to roughly detect
the pH of the preparation of 5-6.
[0199] The control formulation FLL-15-53-2 is the corresponding
formulation lack of the API.
[0200] Formulation FLL-15-25-2 is shown in Table 9.
TABLE-US-00009 TABLE 9 Composition of formulation FLL-15-25-2
Formulation FLL-15-25-2 Content Proportions Batch Materials Effects
(mg) % (g) Nib1 API 25.0 0.5% 0.25 cetostearyl solidified oil 550.0
11.0% 5.50 alcohol phase medium chain ordinary oil 450.0 9.0% 4.50
triglycerides phase Tween 60 emulsifier 150.0 3.0% 1.50 Span 80
emulsifier 50.0 1.0% 0.50 dimethyl solvents and 300.0 6.0% 3.00
sulfoxide penetration enhancers for API benzyl alcohol solvents and
450.0 9.0% 4.50 preservatives for API purified water water phase
3025.0 60.5% 30.25 Total, g / 5000.0 100.0% 50.00
[0201] The formulation FLL-15-25-2 of the preparation for external
application is formulated as follows.
[0202] (1) weighing the prescribed amount of API and adding it to
the mixed solvent composed of dimethyl sulfoxide and benzyl
alcohol, shaking and stirring for a while, and placing it in a
water bath at 70.degree. C. for about 19 minutes to obtain an oil
phase solution of the API;
[0203] (2) adding oil phases including medium-chain triglycerides,
cetostearyl alcohol, Tween 60, and Span 80 to the above
API-containing solution, and then heating and melting in a
70.degree. C. water bath to obtain a transparent API-containing
solution; no API was precipitated; and at the same time, heating
the water at 70.degree. C.;
[0204] (3) adding the above water at the same temperature to the
transparent oil phase solution; the whole system became a milky
white emulsion at the moment of the adding; keeping stirring, and
after taking it out, stirring to cool, and finally it became a
milky white cream; API crystals were precipitated as observed under
microscope.
[0205] The control formulation FLL-15-55-2 is the corresponding
formulation lack of the API.
[0206] 3. Protocols
[0207] After adapting to the environment, female BALB/c mice were
randomly divided into groups. Except for the normal control group,
the rest received external treatment with imiquimod ointment (5%)
to induce the establishment of a psoriasis model. Specifically, the
mice were shaved off the same area (2.times.3 cm) of back hair and
applied with 62.5 mg ointment daily for seven consecutive days. The
animals received different treatments, weighed daily, received 70
mg smear treatment once, and recorded with disease progression
score. Grouping information is shown in Table 10. The disease
progression score is evaluated on a scale of 0-4 based on three
indicators, rash, peeling, and thickening (0: no symptoms; 1: mild
symptoms; 2: moderate symptoms; 3: significant symptoms; 4: very
significant symptoms). At the end of the experiment, the animals
were sacrificed, and pathological section analysis was performed on
the skin samples of the back lesions.
TABLE-US-00010 TABLE 10 Groups and Treatments Modeling agent for
Animals external Treatment Dosing Regimen Groups (n) Group Names
use dose Routes Frequencies 1 3 Normal None None None None 2 8
Dexamethasone 62.5 mg 70 mg external once a day topical 5% for 7
treatment group imiquimod consecutive (DEX) ointment, days 3 8
FLL-15-21-2 once a day 70 mg external once a day treatment group
for seven for 7 consecutive consecutive days days 4 8 FLL-15-53-2
70 mg external once a day control group for 7 consecutive days 5 8
FLL-15-25-2 70 mg external once a day treatment group for 7
consecutive days 6 8 FLL-15-55-2 70 mg external once a day control
group for 7 consecutive days
[0208] 4. Results
[0209] 4.1 Body Weight Changes
[0210] As shown in FIG. 20, the weight loss of the dexamethasone
ointment treatment group was more than 25%. Compared with the
external preparation control group, the animal body weight of each
Nib1 external preparation group did not show significant changes,
indicating that the side effects of the two preparations were not
obvious, and their safety was far better than that of dexamethasone
ointment.
[0211] 4.2 Evaluation of the Clinical Symptoms of the Disease
[0212] As shown in FIGS. 21-25, the psoriasis model was
successfully established in mice, showing symptoms of severe red
rash, peeling and thickening of the skin. Nib1 external application
preparation FLL-15-25-2 performed better than FLL-15-21-2 in
reducing rash and skin thickening symptoms, and both were better
than the dexamethasone ointment treatment group in improving the
symptoms of peeling. Overall, the two kinds of external
applications have significant curative effect than the
corresponding control preparation. ****p<0.0001,
***p<0.001.
[0213] 4.3 Pathological Section Results
[0214] The pathological sections of animal skin were stained, and
the 100-fold magnified pictures are shown in FIGS. 26-34. Three
samples were selected for each group. Compared with the healthy
control group, the external application control group showed
pathological changes such as thickening of the epidermis,
vasodilatation, and immune cell infiltration, while the external
treatment group showed significant improvement in the above
symptoms.
[0215] The raw materials and equipment used in the present
invention, unless otherwise specified, are all commonly used raw
materials and equipment in the field; the methods used in the
present invention, unless otherwise specified, are all conventional
methods in the field.
[0216] The above are only preferred embodiments of the present
invention and do not have any limitation on the present invention.
Any simple modifications, changes and equivalent made to the above
embodiments according to the technical spirit of the present
invention still are within the scope of invention.
* * * * *